Devices, systems, and methods for reducing levels of pro-inflammatory or anti-inflammatory stimulators or mediators in blood products

ABSTRACT

Devices, systems, and methods reduce levels of pro-inflammatory or anti-inflammatory stimulators or mediators in blood by selective adsorption. The devices, systems, and methods are useful in situations where abnormal levels of or unregulated or excessive interaction among pro-inflammatory or anti-inflammatory stimulators or mediators occur, or during events that do induce or have the potential for inducing abnormal production of pro-inflammatory or anti-inflammatory stimulators or mediators. The devices, systems, and methods serve to prevent, control, reduce, or alleviate the severity of the inflammatory response and disease states that are associated with abnormal levels of or unregulated or excessive interaction among pro-inflammatory or anti-inflammatory stimulators or mediators.

RELATED APPLICATIONS

[0001] This application is a continuation-in-part of co-pending U.S.patent application Ser. No. 09/832,159, filed Apr. 10, 2001, andentitled “System for Treating Patient with Bacterial Infections,” whichis incorporated herein by reference. This application is also acontinuation-in-part of co-pending U.S. patent application Ser. No.09/829,252, filed Apr. 10, 2001, and entitled “Method of TreatingPatient with Bacterial Infections,” which is also incorporated herein byreference. This application claims, under 35 U.S.C. §120, the benefit ofthe filing date of copending U.S. patent application Ser. No.09/294,224, filed Apr. 19, 1999, and entitled “Method for RemovingBeta-2 Microglobulin from Blood,” which is a continuation-in-part ofU.S. patent application Ser. No. 08/902,727, filed Jul. 30, 1997 (nowU.S. Pat. No. 5,904,663).

FIELD OF THE INVENTION

[0002] This invention relates to devices, systems, and methods forremoving targeted proteins or toxins from the blood, blood products, orphysiologic fluids.

BACKGROUND OF THE INVENTION

[0003] In animals, an inflammatory response occurs when tissues areinjured by bacteria, trauma, toxins, heat, or other agents, which can becollectively referred to as “Inflammatory Agents.” The nature andcharacter of a given inflammatory response is regulated by the complexinteraction of a variety of pro-inflammatory or anti-inflammatorystimulators or mediators, which are synthesized and released by tissue.Known species of pro-inflammatory or anti-inflammatory stimulators ormediators include, but are by no means limited to, cytokines, nitricoxide, thromboxanes, leukotrienes, platelet-activating factor,prostaglandins, kinins, complement factors, superantigens, monokines,chemokines, interferons, free radicals, proteases, arachidonic acidmetabolites, prostacyclins, beta endorphins, myocardial depressantfactors, anandamide, 2-arachidonoylglycerol, tetrahydrobiopterin, andchemicals including histamine, bradykinin, and serotonin. The discoveryof new (i.e., previously unrecognized) species of pro-inflammatory oranti-inflammatory stimulators or mediators occurs almost daily.

[0004] The nature and intensity of inflammatory responses differ,depending on the site which has been invaded, and on the character ofthe Inflammatory Agent(s), and the interaction of pro-inflammatory oranti-inflammatory stimulators or mediators involved.

[0005] The inflammatory response, when regulated and localized, isbeneficial. However, if not regulated and generalized, the inflammatoryresponse can cause significant tissue injury and even death.

[0006] For example, cytokines are a class of proteins produced bymacrophages, monocytes, and lymphocytes in response to viral orbacterial infection, as well as in response to T cell stimulation duringan immune response. Cytokines are normally present in very lowconcentrations in the blood or tissues.

[0007] The structures and activities of cytokines have been the subjectof many studies. It has become apparent that cytokines possess a widespectrum of immunological and non-immunological activities. It is alsoapparent that cytokines affect diverse physiologic functions, such ascell growth, differentiation, homeostasis and pathological physiology.It is clear that cytokines have multiple biological activities andinteract with more than one cell type. Cytokines are also known to becapable of stimulating their own synthesis, as well as the production ofother cytokines from a variety of cell types. This phenomenon is calledthe “cytokine cascade.”

[0008] Cytokine cascades are associated with systemic changes arisingfrom infection and tissue injury and, in this context, they serve amyriad of biological functions. For example, various cytokines,categorized as the interleukins (IL), interferons (IF), and tumornecrosis factor (TNF), are produced during immune and inflammatoryresponses. These cytokines beneficially control various aspects of theseresponses. In this situation, the cytokine cascade mediates normal hostdefense responses, cell regulation, and cell differentiation.

[0009] However, it has been observed that the function of cytokineproduction can become disordered. This can lead to the presence oflarger than normal concentrations of cytokines. When the cytokinecascade becomes disordered, there can be a rapid extension andamplification of the intended localized host response in such a way thatonly one or a few initiating stimuli trigger the eventual release andparticipation of scores of host mediators. Although a number of featuresof the host response assist in fighting off invasion, an overly robustor poorly modulated endogenous response can rapidly accelerate toproduce other profound alterations in host homeostasis at the cellular,tissue, and systemic levels. As a result, cytokine expression in aregion of the body where tissues or organs are legitimately subject tobacterial infection or an immune response challenge, can, whendisordered, lead to unwanted destruction of healthy tissue elsewhere inthe body. Larger than normal concentrations of certain cytokines cancause disease and other deleterious health effects, some of which can belethal.

[0010] For example, a disordered cytokine cascade that leads to theincreased presence of the cytokines IL-1 and TNF can, alone or incombination, cause a state in animals clinically identical to “septic”shock. It is recognized that septic shock arises due to the individual,combined, and concerted effects of a large number of cytokines. It is acondition inflicting more than 450,000 Americans every year.Cytokine-induced septic shock can be brought about by infection by avariety of microorganisms, including not only bacteria but also viruses,fungi, and parasites. Septic shock can also be initiated by hostresponse to invasion in general, such as by cancer or as a result ofmajor surgery or trauma. Septic shock is a potentially lethalcytokine-mediated clinical complication against which there is nogenerally effective therapeutic approach.

[0011] One of the best studied examples of cytokine-induced septic shockis the case of infection by gram-negative bacteria. It is believed thatthe appearance of bacterial endotoxins, such as lipopolysaccharide(LPS), in the host bloodstream leads to the endogenous production of avariety of host factors that directly and indirectly mediate thetoxicity of LPS. These host-derived mediators include many nowwell-recognized inflammatory cytokines, as well as endocrine hormones,in addition to a number of other endogenous factors such as leukotrienesand platelet activating factor. Among the interacting factors thattogether comprise the cytokine cascade, the cytokine TNF alpha isbelieved to be the most important identified to date. During the ensuingcytokine cascade, the mediators that appear early in the invaded hostare thought to trigger the release of later appearing factors. Many ofthe cytokine mediators not only exert direct functions at the targetedtissues, but also at other local and remote tissues, where subsequentresponses to other mediators produced during the cascade occur, and soon. The result, if unchecked, can be a multifaceted pathologicalcondition, which is characterized most prominently by deleterioushemodynamic changes and coagulopathy leading to multiple organ failureand, often, to death.

[0012] Multiple attempts have been made and still many others arecurrently underway to block specific mediators of this response. Theseattempts have been relatively unsuccessful. Therapy aimed at singlemediators cannot effectively attenuate the entire response. Furthermore,it is the duration rather than the intensity of inflammation thatcorrelates best with outcome, in that the longer the duration ofover-expression of proinflammatory cytokines the higher the mortality.Systemic inflammation results in organ injury which results in theprolongation of the inflammatory response and thus, more organ injury.

[0013] Less lethal but just as profound physiologic effects can occur asa result of abnormal production of certain cytokines, without thepresence of exogenous bacterial toxins. As one example, cytokineTNF-alpha has been found to be an anti-tumor cytokine. As a result,TNF-alpha has been expected to be useful as an antitumor agent. However,it has been discovered that TNF-alpha is identical with cachectin, whichis a cachexia-inducing factor. The disordered production of TNF-alphahas also been correlated with, not only septic shock, but the incidenceof rheumatoid arthritis, adult respiratory distress syndrome (ARDS), theseverity of viral hepatitis, myocardial ischemia, and the inhibition ofmyocardial contraction. Also, TNF has recently been shown to be involvedin initiating the expression of human immunodeficiency virus in humancells that carry latent virus, which could be a contributing factor inthe expression of latent AIDS virus in certain individuals. Furthermore,a correlation between the TNF level in the blood and blood pressure hasalso been observed. As TNF levels increase, blood pressure decreases,which can lead to serious complications such as kidney failure.

[0014] It has also been observed that TNF-alpha also has an activity ofstimulating production of other types of cytokines, such as IL-1, etc.It is known that the cytokine IL-1 is an important agent for inducingand transmitting the systemic biological response against infection andinflammation. IL-1 induces the usual, desirable responses observed ininflammation in general, such as fever, increase of leukocytes,activation of lymphocytes, induction of biosynthesis of acute phaseprotein in liver. It also known that this cytokine has a strongantitumor activity.

[0015] However, when IL-1 is produced in abnormally larger amounts, itmay contribute to the severity of chronic inflammatory diseases, such asrheumatoid arthritis. Thus, the abnormal activation of various cytokinessuch as the interleukins (IL) and tumor necrosis factor (TNF) isbelieved responsible for the tissue damage and pain that occurs invarious inflammatory conditions like rheumatoid arthritis. In rheumatoidarthritis, levels of TNF, IL-1, IL-6 and IL-8 increase dramatically andcan be detected in the synovial fluid. The cytokine cascade induced byexpression of these cytokines results in depressed lipoproteinmetabolism as well as bone and cartilage destruction.

[0016] As another example, the cytokine IL-6 plays an important role inantibody production in B cells. The cytokine IL-6 also is an importantfactor in body systems, e.g., the hematopoietic system, nervous system,and the liver, as well as in immune system. For example, IL-6 iseffective for inducing proliferation and differentiation of T cells,inducing the production of protein at acute phase by acting on hepaticcells, and promoting the growth of cells in bone marrow.

[0017] However, it has also been observed that there is a correlationbetween the abnormal secretion of IL-6 and various disease states, e.g.,autoimmune diseases, such as hypergammaglobulinemia, chronic articularrheumatism, and systemic lupus erythematosus; the abnormal state ofpolyclonal B cells, as well as in the development of the abnormal stateof monoclonal B cells such as myeloma cells; Castleman's diseaseaccompanied with tumor of the lymph nodes, for which the cause isunknown; primary glomerular nephritis; and the growth of mesangialcells.

[0018] As yet another example, in bacterial infections, cytokines suchas IL-8 act as a signal that attracts white blood cells such asneutrophils to the region of cytokine expression. In general, therelease of enzymes and superoxide anions by neutrophils is essential fordestroying the infecting bacteria. However, if cytokine expressioncauses neutrophils to invade, for example, the lungs, release ofneutrophil enzymes and superoxide anion can result in the development ofadult respiratory distress syndrome (ARDS), which can be lethal.

[0019] Despite their diverse and myriad functions, all cytokines shareone common feature. They are all within a narrow size and molecularweight range of 8 to 28 kilodaltons. This size characteristic isextremely important for the clearance of cytokines from the blood. Inthis range, cytokines are effectively cleared by the liver and also thekidney, which clears all proteins below 50 kilodaltons in size. Animbalance between cytokine production and cytokine removal can causedamage to the liver and kidney.

[0020] In disease states where the kidney has failed—which is often thecase in septic shock—hemodialysis or hemofiltration membranes are usedas substitutes for the glomerular membrane of the kidney. However,artificial membranes are severely limited in their ability to clearcytokines from the blood due to their inadequate porosity. In fact, thepredominant mechanism by which these membranes remove cytokines inclinical practice is not filtration, but rather nonspecific surfaceadsorption (J. Am Soc Nephrol 1999 April; 10(4): 846-53, Cytokineremoval during continuous hemofiltration in septic patients, De Vriese AS, Colardyn F A, Philippe J J, Vanholder R C, De Sutter J H, Lameire NH). Typically these membranes have 0.5 to 2 square meters of surfacearea available for adsorption that becomes saturated within the first 30to 90 minutes of treatment (Biomaterials 1999 September; 20(17):1621-34,Adsorption of low molecular weight proteins to hemodialysis membranes:experimental results and simulations, Valette P, Thomas M, Dejardin P).

[0021] It is therefore clear that pro-inflammatory or anti-inflammatorystimulators or mediators, such as cytokines but by no means limited tocytokines, have the potential for both desirable physiologic results andundesirable physiologic results, depending upon the robustness andmodulation of a particular inflammatory response. There is a need forstraightforward and biocompatible devices, systems, and methods thatserve to reduce or otherwise modulate levels of pro-inflammatory oranti-inflammatory stimulators or mediators in instances where abnormallevels of or unregulated or excessive interaction among such materialsexist or can be expected to arise.

SUMMARY OF THE INVENTION

[0022] A detrimental inflammatory response, such as may occur, e.g., inthe continuum from early sepsis to septic shock, or ischemiareperfusion, allograft rejection, chemical/biologic warfare casualties,has traditionally been viewed as a condition in which the localinflammatory response has become generalized and uncontrolled. Immuneeffector cells, especially neutrophils, possess potent cytotoxiccapacity and when unchecked, this response can cause significant tissueinjury.

[0023] However, while this traditional view is true, these intenseinflammatory response conditions may also be viewed as a syndrome ofimmune suppression. Immune effector cells become dysfunctional and areno longer capable of normal immune surveillance. Such a conditionresults in increased susceptibility to recurrent infection, prolongedinflammation and continued tissue injury. This condition can be referredto as “immuno-paralysis” and can be easily demonstrated. When eitherintact septic animals or whole blood taken from septic patients isexposed to an inflammatory stimulus (e.g. endotoxin) the normal hostresponse is severely inhibited.

[0024] From this perspective, therapy aimed at reducing an inflammatoryresponse by targeting removal of some of the pro-inflammatory stimulusmay not restore normal immune responsiveness and thus, may not improveoutcome. Instead, a more desirable immune modulating strategy is to usea biocompatible adsorption medium to selectively adsorb a broaderspectrum of pro-inflammatory or anti-inflammatory stimulators ormediators, which may include but is not neccesarily limited tocytokines, and to thereby restore immunologic stability, rather thanindiscriminately inhibiting or stimulating one or another component.Such a strategy counters the immunologic instability of sepsis and otherintense inflammatory response conditions by reducing the number, andthus the activity, of a wide array of both pro- and anti-inflammatorymolecules. Such a strategy would “auto-regulate” itself, such that asone component of the response increased so too would the effect on thatcomponent. Finally, the desirable strategy might well be limited in itseffect to the circulating pool of mediators rather than influencing thetissue levels where their activity may be beneficial.

[0025] The invention provides devices, systems, and methods for reducinglevels of cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators in the blood, desirably wholeblood, or blood products, or physiologic fluids in situations whereabnormal levels of or unregulated or excessive interaction among suchstimulators or mediators occur, or during events that do induce or havethe potential for inducing abnormal production of or unregulated orexcessive interaction among such stimulators or mediators. The devices,systems, and methods serve to prevent, control, reduce, modulate, oralleviate the severity of many physiologic conditions and disease statesthat are associated with abnormal levels of or unregulated or excessiveinteraction among pro-inflammatory or anti-inflammatory stimulators ormediators.

[0026] One aspect of the invention provides devices, systems, andmethods for removing cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators from the blood, desirablywhole blood, which are of use in acute situations where abnormal levelsor unregulated or excessive interaction among such stimulators ormediators are present in individuals experiencing infection, orindividuals experiencing an immune response. In such situations, thedevices, systems and methods serve to modulate the inflammatory responseby removing at least some of these stimulators or mediators from bloodcirculation, even as such stimulators or mediators are being produced bythe individual to fight off the infection or invasion. This aspect ofthe invention serves to prevent an overly robust endogenous response,such as occurs, e.g., during septic shock. The devices, systems, andmethods can be used alone or in combination with other forms oftreatment targeted to the treatment of the bacterial infection and/orimmune response.

[0027] Another aspect of the invention provides devices, systems, andmethods for removing cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators from the blood, desirablywhole blood, which are of use in situations where abnormal levels of orunregulated or excessive interaction among such stimulators or mediatorsare or may be present, or which involve events that do induce or havethe potential for inducing abnormal production of or unregulated orexcessive interaction among such stimulators or mediators in certain “atrisk” individuals undergoing or about to undergo surgery, e.g., fortreatment of burns or cardiac conditions; or for organ transplantationor reconstructive surgery, or other episodes involvingischemia-reperfusion injury. Other like situations, where abnormallevels of or unregulated or excessive interaction among such stimulatorsor mediators are or may be present, or which involve events that doinduce or have the potential for inducing abnormal production of orunregulated or excessive interaction among such stimulators ormediators, include certain “at risk” individuals who have experiencedtrauma, such as burns, or “the crush syndrome.” In such situations, thedevices, systems, and methods serve to reduce the population of suchstimulators or mediators by removing at least some of such stimulatorsor mediators from the blood circulation. This aspect of the inventionalso serves to modulate the inflammatory response by removing at leastsome pro-inflammatory or anti-inflammatory stimulators or mediators fromthe blood circulation, even as such stimulators or mediators are beingproduced by the individual in response to the surgery or trauma. Thisaspect of the invention serves to prevent an overly robust endogenousresponse, to prevent, e.g., septic shock or other conditions that mayoccur.

[0028] Another aspect of the invention provides devices, systems, andmethods for removing cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators from the blood, desirablywhole blood, which are of use in situations where abnormal cytokinelevels are present in certain “at risk” individuals, whose chronicdisease states are caused by or otherwise correlate with increasedinflammatory activity. Such disease states include, e.g., rheumatoidarthritis; or lung disease such as emphysema or asthma; or pulmonaryfailure; or adult respiratory distress syndrome (ARDS); viral hepatitis;or myocardial ischemia; or autoimmune disease; AIDS; or as a result ofaccidental or intentional exposure to biological or chemical agents,such as anthrax. In such situations, the devices, systems, and methodsserve to reduce the population of cytokines or or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators byremoving such stimulators or mediators from the blood circulation. Thisaspect of the invention serves to treat a given disease condition bylessening the abnormal population of cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators, which isknown or suspected of contributing to severity of the disease condition.The devices, systems and methods can be used alone or in combinationwith other treatment modalities for the disease condition.

[0029] Another aspect of the invention provides devices, systems, andmethods for removing cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators from the blood, which are ofuse in other events that do induce or have the potential for inducingproduction of such stimulators or mediators due to extracorporeal bloodprocessing, handling, or storage. These events can lead to an incidentalor “obligatory” activation of the immune system due to subjecting theblood to extracorporeal treatment, pumping, or storage, e.g., forcentrifugal or membrane blood separation; or for hemodialysis orhemofiltration; or for oxygenation. This obligatory activation of theimmune system can activate production of cytokines or or other speciesof pro-inflammatory or anti-inflammatory stimulators or mediators in theblood as it undergoes extracorporeal treatment, handling, or storage.The increased presence of cytokines or other species of pro-inflammatoryor anti-inflammatory stimulators or mediators in the treated, handled,or stored blood or blood product can, upon re-infusion, generate anincidental inflammatory response in the recipient's system, or at leastcan contribute to an incidental abnormal level of cytokines or otherspecies of pro-inflammatory or anti-inflammatory stimulators ormediators in the recipient. In such events, the devices, systems andmethods serve to reduce the population of cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators byremoving such stimulators or mediators from the treated, handled, orstored blood or blood product. This aspect of the invention serves toprevent incidental inflammatory response conditions or disease states asa result of otherwise beneficial blood treatment, handling or storage,by lessening the population of cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators presentin the re-infused blood or blood product.

[0030] The devices, systems, and methods that embody features of theinvention also make it possible to restore a normal balance betweenpro-inflammatory stimulators or mediators and anti-inflammatorystimulators or mediators. For example, during a cytokine cascade,pro-inflammatory cytokines are typically generated in larger numbers inproportion to anti-inflammatory cytokines. In situations where abnormalcytokine levels exist, the removal of cytokines according to theinvention will tend to remove more pro-inflammatory cytokines thananti-inflammatory cytokines, and thereby aid in maintaining a morenormal balance between the two.

[0031] Another aspect of the invention provides devices, systems, andmethods for removing cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators from physiologic fluids. Forexample, spent peritoneal dialysis solution can carry cytokines or otherspecies of pro-inflammatory or anti-inflammatory stimulators ormediators. Systems and methods exist for regenerating spent peritonealdialysis solution withdrawn from a patient, by removing waste and uremictoxins from the spent solution, as well as introducing electrolytes andbuffering materials into the spent solution. In this way, freshperitoneal dialysis solution can be recreated, obviating the need forbagged replacement solutions. In such situations, the devices, systems,and methods that embody this aspect of the invention remove cytokines orother species of pro-inflammatory or anti-inflammatory stimulators ormediators from the peritoneal dialysis solution, before, during, orafter solution regeneration. This aspect of the invention serves toprevent incidental inflammatory response conditions or disease states asa result of exchange of spent peritoneal dialysis solution withregenerated peritoneal dialysis solution.

[0032] As another example, organs harvested for transplantation, e.g.,kidney, liver, or heart, are typically stored for period of time in asuitable preservation solution until transplantation takes place.Storage of the organ in preservation solution can lead to the generationof cytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators, which accumulate in the preservation solution.In such situations, the devices, systems, and methods that embody thisaspect of the invention remove cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators from thepreservation solution during organ storage and/or before transplantationof the organ occurs. In this way, the invention serves to prevent or atleast ameliorate inflammatory response conditions or disease states as aresult of organ transplantation.

[0033] As yet another example, body fluids that are removed from andthen recycled back to the body during a given treatment modality cancarry cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators, or cytokines or otherspecies of pro-inflammatory or anti-inflammatory stimulators ormediators can be generated as a result of such treatment modalities.Treatment systems and methods exist for removing and recycling suchfluids, e.g., lymphatic fluid, synovial fluid, spinal fluid, orcerebrospinal fluid. The devices, systems, and methods that embody thisaspect of the invention can be used in association with such treatmentmodalities, to remove cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators from the body fluids before,during, or after primary treatment.

[0034] In preferred embodiments, the devices, systems, and methodsremove cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators from the blood by selectiveadsorption. Desirably, the selective adsorption medium is characterizedby a biocompatibility index that reflects a negligible production ofcytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators in the blood as a result of exposure to themedium. Thus, the adsorption medium, which beneficially serves to removecytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators from the blood, does not itself produce anoffsetting result of generating additional cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators.

[0035] Other features and advantages of the inventions are set forth inthe following specification and attached drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0036]FIG. 1 is a schematic view of a system for removing cytokines orother species of pro-inflammatory or anti-inflammatory stimulators ormediators from the blood in acute or chronic or other “at risk”situations;

[0037]FIG. 2 is a schematic view of a system for removing cytokines orother species of pro-inflammatory or anti-inflammatory stimulators ormediators from the blood during an extracorporeal blood processingprocedure, such as blood separation, dialysis, hemofiltration, orextracorporeal oxygenation;

[0038]FIG. 3 is a side section view of a unitary, extracorporeal devicecontaining an adsorption medium for removing cytokines or other speciesof pro-inflammatory or anti-inflammatory stimulators or mediators fromthe blood;

[0039]FIG. 4A is a side view of an exchangeable device that can becoupled to a conventional intravenous blood access catheter for thepurpose of removing cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators from the blood;

[0040]FIG. 4B is a side view of the exchangeable device shown in FIG. 4Aafter being coupled to a conventional intravenous blood access catheterfor the purpose of removing cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators from theblood;

[0041]FIG. 5 is a side section view of an intravenous catheter having awall that is impregnated with an adsorption material that removescytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators from the blood;

[0042]FIG. 6 is a side section view of an intravenous catheter having anintegrally formed chamber containing an adsorption medium that removescytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators from the blood;

[0043]FIG. 7 is a side view of an indwelling catheter having an in-linedevice that contains an adsorption medium for removing cytokines orother species of pro-inflammatory or anti-inflammatory stimulators ormediators from the blood, making possible an ambulatory treatmentregime;

[0044]FIG. 8 is a side section view of a composite treatment modulewhich integrates a device for removing cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators from theblood with a blood processor, the removal device being shown connectedby intermediate tubing downstream from the blood processor;

[0045]FIG. 9 is a side section view of a composite treatment modulewhich integrates a device for removing cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators from theblood with a blood processor, the removal device being shown connectedby intermediate tubing upstream from the blood processor;

[0046]FIG. 10A is a side section view of a composite treatment modulewhich integrates a device for removing cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators from theblood with a blood processor, the removal device and the blood processorcomprising separate units adapted to be joined together for use;

[0047]FIG. 10B is the composite treatment module shown in FIG. 10B afterbeing joined together for use;

[0048]FIG. 11 is a side section view of a composite treatment modulewhich integrates a device for removing cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators from theblood with a blood processor, the module comprising a common housingcompartmentalized into two chambers, one chamber containing the bloodprocessing component and the other chamber containing an adsorptionmedium for removing cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators from the blood beingprocessed;

[0049]FIG. 12 is a side section view of an adsorption particle that canbe used in association with the systems shown in FIGS. 1 and 2 forselectively adsorbing cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators from the blood;

[0050]FIG. 13 is a side section view of a device that is usable inassociation with the systems shown in FIGS. 1 and 2 for removing bothcytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators and other targeted proteins or toxins from theblood;

[0051]FIG. 14 is a schematic view of a system for removing cytokines orother species of pro-inflammatory or anti-inflammatory stimulators ormediators from a physiologic fluid, which takes the form of regeneratedperitioneal dialysis solution;

[0052]FIG. 15 is a schematic view of a system for removing cytokines orother species of pro-inflammatory or anti-inflammatory stimulators ormediators from a physiologic fluid, which takes the form of preservationsolution for an organ awaiting transplantation;

[0053]FIG. 16 is a schematic diagram of a test system that is used tocharacterize the biocompatibility index of a given adsorbant medium;

[0054]FIG. 17 is a graph plotting the cytokine response in the blood ofa sepsis animal model as a result of treatment using a biocompatibleadsorbant medium;

[0055]FIGS. 18A, 18B, and 18C are graphs showing the variations in bloodcell counts for red blood cells, white blood cells, and platelets,respectively, during passage of 25 ml of the blood through a treatmentdevice containing an adsorbant medium useful for removing cytokines fromthe blood;

[0056]FIG. 19 is a graph showing the variations in PMN elastaseconcentrations (indicative of leukocyte activation) during passage of 25ml of the blood through a treatment device containing an adsorbantmedium useful for removing cytokines from the blood;

[0057]FIG. 20 is a graph showing the variations in LDH concentrations(indicative of hemolysis) during passage of 25 ml of the blood through atreatment device containing an adsorbant medium useful for removingcytokines from the blood;

[0058]FIG. 21 is a graph showing the variations in C3a-desArgconcentrations(indicative of complement activation) during passage of 25ml of the blood through a treatment device containing an adsorbantmedium useful for removing cytokines from the blood;

[0059]FIG. 22 is a graph showing the variations in TAT concentrations(indicative of coagulation) during passage of 25 ml of the blood througha treatment device containing an adsorbant medium useful for removingcytokines from the blood; and

[0060]FIG. 23 is a chart summarizes the results of hemocompatibilitytesting conducted by Bosch et al of a polyacrylate gel adsorbantmaterial (for the selective adsorption of low-density lipoproteins),based upon contact with blood that was anticoagulated either only withheparin or with a mixture of heparin and citrate.

[0061] The invention may be embodied in several forms without departingfrom its spirit or essential characteristics. The scope of the inventionis defined in the appended claims, rather than in the specificdescription preceding them. All embodiments that fall within the meaningand range of equivalency of the claims are therefore intended to beembraced by the claims.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0062] I. Systems and Methods for Removing Cytokines From the Blood

[0063] Cytokines and other species of pro-inflammatory oranti-inflammatory stimulators or mediators are low molecular weightproteins that are present in the blood. They are typically produced bythe body in response to viral or bacterial infection and in response animmune response. Cytokines are also known to be capable of stimulatingtheir own synthesis, as well as the production of other cytokines from avariety of cell types. Cytokines are normally present in very lowconcentrations in a tissue, but, due to an over-robust and unmodulatedcytokine cascade or other causes, cytokines can be present in abnormalconcentrations. In abnormal concentrations, cytokines can cause diseaseor septic shock.

[0064] As used in this Specification, the term “cytokine” as used hereinis meant any secreted polypeptide that affects the functions of othercells, and is a molecule which modulates interactions between cells inthe immune or inflammatory response. Cytokines are soluble protein andpeptide humoral regulators. Type-1 cytokines are produced by Type-1helper cells, e.g. IL2, IFN-gamma, IL12 and TNF-beta, and Type-2cytokines are produced by Type-2 helper cells, e.g. IL4, IL5, IL6, IL10,and IL13. These may be pro-inflammatory or anti-inflammatory,chemotactic, paracrine, endocrine, juxtacrine, autocrine, andretrocrine. They also function as growth factors and apoptosis factors,involved in inflammation, septic shock, the systemic inflammatoryresponse syndrome (SIRS), acute phase reactions, wound healing andneuroimmune networks. Others include IFN-alpha, -beta, -gamma, -omega,IL2-9, GCSF, MCSF, GMCSF, PGDF, IL-1-alpha, -beta, TNF-alpha, FGF, IL8,IP10, PF4, GRO, 9E3 and recombinant cytokines, muteins, and proteinmimetics. Cytokines also comprise B-cell differentiation factors (BCDF),Bcell growth factors (BCGF), mitogenic cytokines, chemotactic cytokines(chemokines), colony stimulating factor (CSF), angiogenesis factors,t-cell replacing factor (TRF), heparin binding growth factor (HBGF),substance p (tachykinin), and kinins.

[0065] A. Acute or “At Risk” Conditions

[0066]FIG. 1 generically shows a system 10 for removing cytokines 12 orother species of pro-inflammatory or anti-inflammatory stimulators ormediators (which are generally identified by circled C's in FIG. 1) fromthe blood 14, and desirably from whole blood. In the illustratedembodiment, the blood 14 emanates from a blood source 16. In theembodiment shown in FIG. 1, it is contemplated that the blood source 16comprises the circulatory system of an individual.

[0067] In FIG. 1, it is also contemplated that the cytokines 12 or otherspecies of pro-inflammatory or anti-inflammatory stimulators ormediators exist in the blood in abnormal levels, or at least thepotential exists that the individuals levels of cytokines or otherspecies of pro-inflammatory or anti-inflammatory stimulators ormediators may become abnormal, i.e., reach levels above normalphysiologic levels, or otherwise create an unregulated or excessiveinflammatory response interaction. Accordingly, as shown in FIG. 1, thesystem 10 includes a device 18 through which the blood 14 is circulatedfrom the source 16 for the purpose of removing at least a portion of thepopulation of cytokines 12 or other species of pro-inflammatory oranti-inflammatory stimulators or mediators carried in the blood 14. Theremoval of cytokines 12 or other species of pro-inflammatory oranti-inflammatory stimulators or mediators from the blood 14 serves tocontrol, reduce, or alleviate the severity of many physiologicconditions and disease states that are associated with abnormal cytokinelevels or an unregulated or excessive inflammatory response. As shown inFIG. 1, the cytokine-depleted blood 20 is returned to the individualblood source 16.

[0068] The cytokines 12 or other species of pro-inflammatory oranti-inflammatory stimulators or mediators may be present or pose thepotential to exist in the blood 14 in abnormal levels for variousreasons. For example, the individual may be in an acute condition,experiencing infection or an immune response. In this situation,cytokines 12 or other species of pro-inflammatory or anti-inflammatorystimulators or mediators are being generated by the individual to fightthe infection or invasion. The concurrent removal of cytokines 12 orother species of pro-inflammatory or anti-inflammatory stimulators ormediators by the device 18 modulates the inflammatory response, e.g., toprevent the onset of a condition on a continuum from sepsis to septicshock or damage to tissue elsewhere in the body. Alternatively, theindividual may be experiencing a condition on a continuum from sepsis toseptic shock. In this situation, the concurrent removal of cytokines 12or other species of pro-inflammatory or anti-inflammatory stimulators ormediators by the device 18 modulates the inflammatory response toterminate the deleterious hemodynamic changes and coagulopathyoccasioned by septic shock, to prevent organ failure and death. Ineither situation, one prevention and the other treatment, the removal ofcytokines 12 or other species of pro-inflammatory or anti-inflammatorystimulators or mediators by the device 18 aims to prevent an overlyrobust and possible lethal endogenous response.

[0069] The device 18 can be used alone or in combination with otherforms of treatment targeted to the treatment of the bacterial infectionand/or immune response and/or septic shock. Examples of other forms oftreatment that can be used in combination with the device 18 includeantibiotics, antimicrobial agents, antifungal agents, antiviral agents,and specific compounds such as activated protein-C.

[0070] In another embodiment, the cytokines 12 or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators may bepresent in abnormal levels because the individual possesses an “at risk”acute or chronic disease state, which is caused by or otherwisecorrelate with increased physiologic cytokine activity or an unregulatedinflammatory response. Such disease states include, e.g., rheumatoidarthritis; or lung disease such as emphysema or asthma; or pulmonaryfailure; or adult respiratory distress syndrome (ARDS); viral hepatitis;or myocardial ischemia; or autoimmune disease; AIDS; or as a result ofexposure to biological or chemical agents, such as anthrax. The removalof cytokines 12 or other species of pro-inflammatory oranti-inflammatory stimulators or mediators by the device 18 reduces thepopulation of cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators to treat the severity of thedisease condition. The treatment of the individual using the system 10can be under acute conditions (due to the presence of severe symptoms).The treatment using the system 10 can also be under chronic conditions,as a part of scheduled, periodic treatment of the disease condition.

[0071] In either situation, the device 18 can be used alone or incombination with other treatment modalities beneficial for the diseasecondition. Examples of other forms of treatment that can be used incombination with the device 18 include antibiotics, antimicrobialagents, antifungal agents, antiviral agents, and specific compounds suchas activated protein-C.

[0072] In another embodiment, the cytokines 12 or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators may bepresent in abnormal levels, or may potentially rise to abnormal levels,because the individual is “at risk” due to present or contemplatedsurgery, e.g., for treatment of burns or cardiac conditions; or fororgan transplantation or reconstructive surgery, or other episodesinvolving ischemia-reperfusion injury. Alternatively, the individual canbe “at risk” because of trauma, such as burns, or “the crush syndrome,”which may or may not require corrective surgery. In such situations,cytokines 12 or other species of pro-inflammatory or anti-inflammatorystimulators or mediators have likely already been generated by theindividual due to injury and trauma to the body, and resultingcorrective surgery is likely to maintain or even increase generation ofcytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators. The removal of cytokines 12 or other speciesof pro-inflammatory or anti-inflammatory stimulators or mediators by thedevice 18, after the trauma and either before surgery, or duringsurgery, or after surgery, or a combination thereof, reduces thepopulation of cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators, to modulate the inflammatoryresponse. The removal of cytokines 12 or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators by thedevice 18 aims to prevent an overly robust and possible lethalendogenous response, to prevent, e.g., septic shock or other unregulatedor excessive inflammatory response conditions that may occur. Thetreatment using the system 10 can occur under acute conditions (i.e., asan adjunct to the surgical procedure or other treatment of the trauma),and/or under chronic conditions, as a part of a scheduled rehabilitationprogram following the trauma or surgery.

[0073] In either situation, the device 18 can be used alone or incombination with other treatment modalities beneficial for the injuryand surgical procedure. Examples of other forms of treatment that can beused in combination with the device 18 include antibiotics,antimicrobial agents, antifungal agents, antiviral agents, and specificcompounds such as activated protein-C.

[0074] B. Extracorporeal Blood Processing

[0075]FIG. 2 show a blood processing system 20 that removes cytokines 12or other species of pro-inflammatory or anti-inflammatory stimulators ormediators from the blood 14 as it undergoes extracorporeal processing.In use, the system 20 is intended to convey the blood from a bloodsource 22 (typically, the circulatory system of a donor or patient) toan extracorpreal blood processing assembly 24. After processing, all ora portion of the blood is either returned to the circulatory system ofthe individual donor or patient, or retained for storage and subsequenttransfusion to the same donor or patient, or to another recipient, or acombination thereof.

[0076] Typically, the functional components of the blood processingassembly 24 are a blood inlet line 26, a blood processor 28, and a bloodoutlet line 27. The blood from the donor or patient is conveyed by theblood inlet line 26 to the processor 28 for the desired processing.After processing, the blood is convey from the processor 28 by the bloodoutlet line 27. The system 20 may continuously or intermittently conveythe blood to and from the blood processing assembly 24, typically usingone or more peristaltic pumps (designated P in FIG. 2).

[0077] Depending upon the objectives of the processing, the blood outletline 27 can be coupled directly to the donor or patient, so that theprocessed blood is returned directly to that individual. In otherprocessing schemes, all or a portion of the processed blood is retainedfor storage and not returned to the donor or patient. In thisarrangement, the blood outlet line 27 also communicates with a bloodstorage container 32.

[0078] The blood processing assembly 24 can be constructed in variousways and perform different processing functions.

[0079] 1. Blood Separation

[0080] The blood processing assembly 24 can serve to separate wholeblood into plasma and cellular blood components (i.e., blood products),typically, red blood cells and platelets. In this arrangement, the bloodprocessing assembly 24 can comprise a centrifuge or a membrane thatseparates whole blood into its components. Depending upon the objectivesof the device, all or some of the components are collected for storageand later transfusion. The components that are not collected aretypically returned to the blood donor.

[0081] For example, in a process called plasmapheresis, plasma can becollected in an extracorpeal circuit for later fractionation to harvesttherapeutic plasma proteins, e.g., Factor VIII. The remaining cellularcomponents (red blood cells and platelets, along with the leukocytes)are returned to the blood donor.

[0082] Or, in a process called plasma exchange, plasma can be collectedin an extracorpreal circuit. The plasma is discarded, and the cellularcomponents (red blood cells, leukocytes, and platelets) are returned tothe blood donor, along with a plasma-replacement fluid. Alternatively,the plasma itself can be treated by immunoadsorption, to removeundesired materials—e.g., antibodies—which is then returned with thecellular components to the individual.

[0083] As another example, in a process called plateletpheresis, theblood is circulated through an extracorpreal path through a centrifuge,which centrifugally separates and collects concentrated platelets forlater transfusion. The remaining cellular components and plasma arereturned to the donor. Alternatively, a volume of red blood cells orplasma, or both, can be retained for storage and later transfusion torecipients undergoing blood component therapy.

[0084] There are many other types of blood cell harvesting procedures inaddition to plateletpheresis, where a targeted blood cell is collected,e.g., leukopheresis. There are also many other types of blood processingprocedures in general, such as photopheresis (for inactivation of viralpathogens) or hypothermia, which circulate blood in extracorporeal pathsto achieve desired therapeutic or diagnostic objectives.

[0085] The preceding examples process the blood on-line, that is, whilethe donor remains coupled to the system. In another arrangement, calledmanual collection, a unit of whole blood is drawn into a plastic bloodcollection bag, to which one or more plastic satellite bags areintegrally connected. These arrangements of integrally connected bagsare called multiple blood bag systems. After the unit of whole blood isdrawn, the donor is disconnected. The whole blood is then subjected tooff-line centrifugation while in the blood collection bag. Thecentrifugation separates the whole blood into layers of red blood cellsand plasma, with an intermediate layer of leukocytes. The plasma can beeither rich in platelets or poor in platelets, depending upon thecentrifugal forces applied. The plasma component is transferred into asatellite bags, leaving the red blood cells (and leukocytes) behind inthe blood collection bag. If rich in platelets, the plasma component canbe further centrifugally separated in the satellite bag to obtainconcentrated platelets. The components are stored in the individualplastic bags for later transfusion to recipients undergoing bloodcomponent therapy.

[0086] 2. Hemodialysis or Hemofiltration

[0087] The blood processing assembly 24 can also carry out processes,called hemodialysis or hemofiltration, which emulate normal kidneyactivities for an individual whose renal function is impaired orlacking.

[0088] During hemodialysis, the blood from an individual is conveyed inan extracorporeal path along one side of a membrane. A dialysate iscirculated on the other side of the membrane and forms a concentrationdifferential across the membrane. Liquid and uremic toxins carried inthe blood are drawn by the concentration differential across themembrane and out of the blood.

[0089] During hemofiltration, the blood from an individual is conveyedin an extracorporeal path along a semipermeable membrane, across which apressure difference (called transmembrane pressure) exists. The pores ofthe membrane have a molecular weight cut-off that can pass liquid anduremic toxins carried in the blood.

[0090] In both hemodialysis and hemofiltration, the membrane pores donot pass formed cellular blood elements and plasma proteins. Thesecomponents are retained and returned to the individual with thetoxin-depleted blood, along with a replacement fluid. The replacementfluid restores, at least partially, a normal physiologic fluid andelectrolytic balance to the blood. Hemodialysis and hemofiltration canbe carried out as individual processes, or in combination.

[0091] A form of hemodialysis is also used to treat individualssuffering from jaundice caused by inadequate liver function or liverfailure. In this indication, the blood carries abnormal levels ofbilirubin, a breakdown product of hemoglobin normally removed by theliver. The blood is passed along one side of a dialysis membrane.Healthy liver cells are located on the opposite side of the membrane.The healthy liver cells remove bilirubin from the processed blood. Inthis treatment, the blood is passed before undergoing dialysis throughan adsorption device (typically contained activated charcoal) to removecertain blood materials that are lethal to liver cells.

[0092] 3. Oxygenation (Cardiopulmonary Bypass)

[0093] The blood processing assembly 24 can alternatively carry out aprocess called oxygenation. Oxygenation is carried out duringcardiopulmonary bypass, during which the blood is circulated outside theheart and lungs while heart surgery occurs. During oxygenation, theblood conveyed from an individual is transported in an extracorporealpath along a membrane across which a oxygen concentration differentialexists. Oxygen from the opposite side of the membrane is transportedinto the blood on the opposite side of the membrane, to emulate lungfunction.

[0094] 4. Removal of Cytokines or Other Species of Pro-Inflammatory orAnti-Inflammatory Stimulators or Mediators

[0095] Extracorporeal processing of the blood in the system 20 maytrigger an incidental or “obligatory” activation of the components ofthe immune system carried by the blood. The sources of this incidentalactivation can include exposure to biomaterials in the inlet and returnlines 26 and 28 or in the blood processing assembly 24 itself. Externalpumping of the blood can also trigger an incidental immune response. Thecentrifugal forces or shear forces developed by passage along a membranecan also trigger an incidental immune response.

[0096] The incidental activation of the immune system occasioned duringblood processing can lead to the incidental generation of cytokines orother species of pro-inflammatory or anti-inflammatory stimulators ormediators. These cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators, to the extent that they areincidentally produced as a result of blood processing, will betransported by the blood that is returned to the donor or patient duringprocessing, or by stored blood delivered to a recipient duringtransfusion. Entering the circulatory system of the donor or otherrecipient, these incidental cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators can serveto raise the levels of cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators in the donor or otherrecipient, and could lead to the generation of further cascades orinflammatory responses, during which further cytokines or other speciesof pro-inflammatory or anti-inflammatory stimulators or mediators andadditional by-products of immune system activation are produced. Thus,processes that provide beneficial results in one respect can lead toincidental, potentially adverse results in another respect.

[0097] The blood processing system 20 therefore includes a device 30that removes cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators from the processed blood.

[0098] In on-line blood processing systems—e.g., those systems in whichthe circulatory system of the donor or patient remains coupled to theprocessor 24 during processing—the device 30 can be coupled in-lineeither upstream or downstream of the processor 24 (in FIG. 2, the device30 is shown positioned in the return line 28 for purposes ofillustration). In this arrangement, cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators areremoved during circulation of the blood through the extracorporealcircuit, thereby leading to reduced levels of cytokines or other speciesof pro-inflammatory or anti-inflammatory stimulators or mediators in theblood returned to the donor or patient.

[0099] In off-line blood processing systems—e.g., where the blood isprocessed after disconnecting the donor from the collection system—or ina system that collects a blood component for later transfusion to arecipient (as FIG. 2 shows)—it is desirable to place the device 30either upstream of the blood component storage bag (as shown in phantomlines in FIG. 2)(so cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators are removed after bloodprocessing and before storage of the blood component) or in atransfusion set coupled to the satellite blood component storage bag (sothat cytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators are removed during the act of transfusion ofthe processed blood component).

[0100] The device 30 serves to reduce the population of cytokines orother species of pro-inflammatory or anti-inflammatory stimulators ormediators by removing cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators from the treated, handled, orstored blood. The device 30 thereby serves to prevent incidentalcytokine-induced or inflammatory response conditions or disease statesas a result of otherwise beneficial blood treatment, handling orstorage, by lessening the population of cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators presentin the returned or re-infused blood. The removal by the device 30 ofcytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators generated as a result of extracorporeal bloodprocessing aims to maintain a status quo condition in the immune systemof the individual undergoing blood processing or the recipient of storedblood.

[0101] II. Devices for Removing Cytokines or Other Species ofPro-Inflammatory or Anti-Inflammatory Stimulators or Mediators From theBlood

[0102] Cytokines and other species of pro-inflammatory oranti-inflammatory stimulators or mediators are low molecular weight,electrically neutral proteins, ranging in size from about 8000 to about28,000 daltons. Cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators can be removed from the bloodby various mechanism, e.g. by selective adsorption, or by ion exchange,or by non-specific adsorption to dialysis membranes. The devices 18 or30 for removing cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators from the blood can thereforebe variously constructed, depending upon the removal mechanism selected.

[0103] In the illustrated embodiment, selective removal by adsorption isthe selected mechanism.

[0104] A. Unitary Extracorporeal Devices

[0105] Either device 18 or 30 can comprise a stand-alone, or unitary,extracorporeal component that can be coupled in-line to blood tubing attime of use.

[0106] In this arrangement (see FIG. 3), either device 18 or 30desirably includes in its most basic form a housing 32. The housing 32contains a medium 34 that removes cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators byadsorption.

[0107] The housing 32 includes an inlet 33 for conveying the blood intothe housing 32 for contact with the adsorption medium 34. The housing 32also includes an outlet 36 for conveying the blood from the housingafter contact with the adsorption medium 34, during which all or aportion of the cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators present are removed.

[0108] Desired characteristics of the adsorption medium 34 will bedescribed in greater detail later.

[0109] The transport of the blood through the adsorption medium 34 inthe housing 32 can be accomplished in various ways, depending in largepart upon the environment in which the device 18 or 30 is used. In theacute or chronic applications described, which involve use of the device18, an external pump can be used to convey the blood through the housing32 to remove cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators.

[0110] Alternatively, blood tubing connected to the inlet 33 of thehousing 32 can be coupled via a suitable blood access to an artery,while blood tubing connected to the outlet 36 of the housing 32 can becoupled by a suitable blood access to a vein, thereby using physiologicblood pressure to convey the blood through the housing 32 to removecytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators.

[0111] When used in association with a blood processing system, whichinvolves use of the device 30, an external pump (identified as P in FIG.2) is typically present to convey the blood through the blood processingassembly 24.

[0112] In this arrangement, the external pump P that serves the bloodprocessing assembly can concurrently provide the pressure to convey theblood through the housing 32 to remove cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators.

[0113] In an alternative embodiment shown in FIGS. 4A and 4B, thehousing 32 can be configured to comprise an exchangeable component 38that can be releasably coupled to a conventional intravenous bloodaccess catheter 40, e.g., of the type widely used in intensive careunits. The exchangeable component 38 provides particular ease of use ineither acute or chronic indications, as above described, as individualsin such circumstances are typically already fitted with intravenousblood access catheters for other purposes. However, the exchangeablecomponents 38 would also provide ease of use in the setting ofextracorporeal blood processing, as the intravenous blood tubingcomprising the blood inlet line 26 or blood outlet line 27 serving theprocessor 28 could be ready modified to include fittings to accommodatequick exchange of the component 38.

[0114] In this arrangement, the inlet 33 and 36 of the exchangeablecomponent 38 and the catheter 40 (or inlet and outlet lines 26 and 27)would include, e.g., convention mating luer fittings 42, to enable quickattachment and removal in-line in the intravenous blood access catheter40 or intravenous blood lines 26/27 serving the processor 28, as FIGS.4A and 4B demonstrate.

[0115] In another alternative embodiment shown in FIG. 5, all or aportion of the wall of an intravenous catheter 44 can be impregnatedwith the adsorption medium 34. In this arrangement, transport of theblood through the catheter 44 exposes the blood to the medium 34 for theremoval of cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators. Alternatively (as shown inFIG. 6), an intravenous catheter 46 can include an integrally formedchamber 48 in which the adsorption medium 34 is housed. Thus, transportof the blood through the catheter 44 exposes the blood to the medium 34for the removal of cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators. In the embodiments shown inFIGS. 5 and 6, the device 18 or 30 forms an integrated part of the bloodtransport path, so that a separate housing 32 per se is not required tocontain the adsorption medium 34.

[0116] B. Ambulatory Applications

[0117] As FIG. 7 shows, either device 18 or 30 can comprise a component50 that is intended to be coupled to an indwelling catheter 52, that issurgically fitted to the individual undergoing treatment. The catheter52 is surgically attached to the circulatory system of the individual,e.g., between an artery and a vein, to form a loop through which theblood continuously circulates. In this arrangement, the component 50carries the adsorption medium 34 that serves to remove cytokines orother species of pro-inflammatory or anti-inflammatory stimulators ormediators from the individual's blood traversing the catheter 52. As apart of an indwelling blood circulation loop, the component 50 removescytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators continuously on a daily basis, as theindividual ambulates and carries on life's activities outside of atreatment facility.

[0118] The component 50 can be configured to be an external or internalexchangeable device that can be releasable coupled to the indwellingcatheter 52, e.g., by use of luer fittings 42, in the manner generallyshown in FIGS. 4A and 4B. Alternatively, the wall of the indwellingcatheter 52 can itself be impregnated with the adsorption medium 34, asgenerally shown in FIG. 5.

[0119] The component 50, in association with an indwelling catheter 52,makes possible a continuous, ambulatory treatment to remove cytokines orother species of pro-inflammatory or anti-inflammatory stimulators ormediators. This treatment modality would have particular application forthose “at risk” individuals whose disease states are caused by orotherwise correlate with chronic, increased physiologic cytokineactivity or other unregulated inflammatory response condition. Thecomponent 50 provides a new form of ambulatory treatment for, e.g.,rheumatoid arthritis; or lung disease such as emphysema or asthma; oradult respiratory distress syndrome (ARDS); or autoimmune disease; orAIDS. The component 50 serves to maintain a reduced population ofcytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators, by continuously removing cytokines or otherspecies of pro-inflammatory or anti-inflammatory stimulators ormediators from the blood circulation. The component 50 can be used aloneor in combination with other treatment modalities for the diseasecondition.

[0120] C. Integrated Composite Devices

[0121]FIGS. 8 and 9 show an absorption device 30 of a type shown in FIG.3, integrally coupled by intermediate tubing 43 to a blood processor 28.Together, the device 30, processor 28, and linking tubing 43 form acomposite blood treatment module 54 that is supplied to a user as anintegrated unit.

[0122] The composite module 54 can be arranged so that the absorptiondevice 30 is integrally coupled in a downstream flow direction to theblood processor 28 (as FIG. 8 shows), or, alternatively arranged, in anupstream flow direction to the blood processor 28 (as FIG. 9 shows). Inyet another arrangement, the adsorption device 30 can be placed bothupstream and downstream of the blood processor 28.

[0123] The module 54 can perform different blood processing functions inassociation with a blood adsorption function, e.g., to remove cytokinesor other species of pro-inflammatory or anti-inflammatory stimulators ormediators, depending upon the operational capabilities of the bloodprocessor 28. The processor 28 can be configured to perform diversefunctions, e.g., hemodialysis, or hemofiltration, or membrane separationof plasma from whole blood, or blood filtering (e.g., to removeleukocytes), or ionic exchange, etc., or combinations thereof.

[0124] As FIGS. 10A and 10B show, the adsorption device 30 can be moreintimately attached to the blood processor 28 to form the module 54without use of intermediate tubing 43. In this arrangement (see FIG.10A), both the adsorption device 30 and processor 28 are manufactured asseparate units. The adsorption device 30 and processor 28 are configuredwith, e.g., a tubular male fitting 56 on the device 30 that mates with afemale fitting 58 in the processor 28. The fittings 56 and 58 couple thedevice 30 and the processor 28 together in fluid flow communication, asFIG. 10B shows.

[0125] Of course, the mating configuration of the fittings 56 and 58 canbe reversed, so that the device 30 includes a female fitting 58 and theprocessor 28 includes the male fitting 56. Furthermore, other attachmentconfigurations, e.g., screw fit, keyed fittings, etc., can be used.Mating stabilization struts 60 may also be provided to further lock thedevice 30 and processor 28 together.

[0126] By manufacturing the adsorption device 30 and separator 28separately, and then joining them together to form an integrated module54, different sterilization processes may be used. For example, thedevice 30 and adsorption medium 34 may be sterilized by a firststerilization process, e.g., hot water or steam or external irradiation,whereas the processor 28 may be sterilized by a second, differentsterilization process, e.g., EtO sterilization. This modular arrangementthereby accommodates the choice of biomaterials for the adsorptionmedium 34 and the functional component of the processor 28 havingdifferent physical properties best suited for their particularfunctional objections, and not constrained by similar sterilizationrequirements. The arrangement shown in FIGS. 8 and 9 also accommodatesdifferent sterilization techniques prior to joining the device 30 andprocessor 28 with the tubing 43.

[0127] As with the embodiments shown in FIGS. 8 and 9, the fittings 56and 58 can configured to join the device 30 in an upstream flowdirection to the blood processor 28, or (as FIG. 10B shows) in adownstream flow direction to the blood processor 28, or at both upstreamand downstream ends of the blood processor 28.

[0128] The device 30 may be integrally coupled to the processor 28during manufacturing, and be supplied to the customer as an integratedmodule 54 (as FIG. 10B shows). Alternatively, the device 30 andprocessor 28 may be supplied separately to the customer (in the mannershown in FIG. 10A), who is instructed to join the adsorption device 30to the processor 28 by plugging the fittings 56 and 58 together at timeof use.

[0129] As FIG. 11 shows, the adsorption device 30 can be even moreintimately associated with the blood processor by placing the processor28 and device 30 within the confines of a single housing 62. The singlehousing 62 has an inlet port 68 and an outlet port 70. In thisarrangement, an interior partition wall 72 in the housing 62compartmentalizes the housing 62 into a first compartment 64 (whichcommunicates with the inlet port 68) and a second compartment 66 (whichcommunicates with the outlet port 70). One or more openings 74 in theinterior wall 72 open flow communication between the first and secondcompartments 64 and 66.

[0130] Each compartment 64 and 66 can contain either the functionalcomponent of the processor 28 or the adsorption medium 34. In theembodiment shown in FIG. 11, the functional component of the processor28 is contained in the first compartment 64, and the adsorption medium34 is contained in the second compartment 66. Of course, the arrangementof the materials contained in the compartments 64 and 66 can bereversed. The housing can also be partitioned to place the adsorptionmedium 34 at both the inlet and outlet sides of the blood processor 28,sandwiching the functional component of the blood processor 28 betweenit.

[0131] This arrangement requires the selection of materials for theprocessor 28 and adsorption medium 34 that accommodate the samesterilization process, e.g., hot water sterilization.

[0132] It should be appreciated that the various composite structures 54just discussed, which join an adsorption device 30 with a bloodprocessor 28, are not limited to a particular adsorption function forthe adsorption device 30. That is, while the adsorption device 30 has beearlier described in this application the context of the removal ofcytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators, the adsorption device 30 can, in associationwith the processor 28, carry out other functions as well. For example,when the processor 28 takes the form of a hemodialyzer, the adsorptiondevice 30 can serve the function of selectively adsorbing middlemolecular weight proteins (e.g., beta-2 macroglobulin) that conventionalhemodialysis membrane do not efficiently remove.

[0133] D. Adsorption Medium

[0134] The adsorption medium 34 can be variously constructed. In theillustrated embodiment (see, e.g., FIG. 3), the adsorption medium 34desirable includes a group of porous polymeric particles 76, which areformed to selectively retain cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators. Takinginto account the physical proportions of cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators, thepolymeric particles 76 of the medium 34 are predominantly mesoporous,with a pore size ranging from 2 to 70 nm, and preferably from 5 to 50nm.

[0135] As FIG. 12 best shows, each polymer particle 76 desirablypossesses a porous hydrophobic core 78. The pores are sized to provideclose contact between the cytokines or other species of pro-inflammatoryor anti-inflammatory stimulators or mediators and the hydrophobicsurface of the pores.

[0136] The surface of the hydrophobic particles 76 can be modified toprovide a hydrophilic coating 80, which imparts a high degree ofbiocompatibility with the human organism, and, in particular, the blood.This biocompatibility can be expressed in terms of a biocompatibleindex, as will be decribed in greater detail later. The hydrophiliccoating 80 is desirably thin and permeable so as to allow penetration ofcytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators to the hydrophobic porous core 78 of theparticles 76.

[0137] The hydrophobic cores 78 of the particles 76 can be composed, forexample, of crosslinked polymeric materials prepared by polymerizationor copolymerization of the following monomers: styrene, ethylstyrene,α-methylstyrene, divinylbenzene, di isopropenyl benzene,trivinylbenzene, alkyl methacrylate as methyl methacrylate, butylmethacrylate. The hydrophilic biocompatible coating 80 of the particles76 can be composed for example of the following materials:polyvinylpyrrolidone, polyhydroxyethyl methacrylate,carboxymethylcellulose, polyurethane.

[0138] In a device of the type shown in FIG. 3, the particles 76 aresized, taking into account the size of the device, to obtain a desiredflow rate through the device. As an example, given a device size of 400ml, the particles 76 are sized greater than 300 μm in diameter topresent an effective surface area to the blood of about 500 m²/gram ofadsorption medium 34 used.

[0139] Particles 76 having the characteristics described alsoselectively adsorb superantigens. Superantigens are low molecular weightproteins that are toxic. Superantigens are produced by organisms and arestrong activators of the immune system and cytokine production. Thepresence of superantigens can therefore also contribute to increasedlevels of cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators. The concurrent removal bythe particles of both cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators and superantigens enhancesthe overall therapeutic function of the adsorption medium 34.

Representative Adsorption Medium EXAMPLE 1

[0140] In one representative embodiment, the adsorption medium 34 caninclude particles or beads formed from hypercrosslinked polystyrene-typeresins. The surface of the beads is desirably modified to preventabsorption of large proteins and platelet and to minimize activation ofblood complement system, without affecting noticeably accessibility ofan inner absorption space of the beads for small and middle-sizedmolecules. The particles or beads can comprise, e.g.,styrene-divinylbenzene copolymers subjected to an extensive crosslinkingin a swollen state with bifunctional crosslinking agents, such asmonochlorodimethyl ether or p-xylylene dichloride. Alternatively, theparticles or beads can comprise styrene-divinylbenzene copolymerssubjected to chloromethylation and post-crosslinking. Alternatively, thematerial can comprise a porous hydrophobic acrylic polymer or amesoporous ethylstyrene-divinylbenzene copolymer.

[0141] The surface modification can be accomplished is various ways,e.g., (i) by depositing on the surface of the particles or beads highmolecular weight poly(N-trifluoroalkoxy) phosphazene, by treating thebeads with a solution of phosphazene in an organic solvent andevaporating the solvent; or (ii) electrostatically binding of heparinfrom its aqueous solution onto the beads whose chloromethyl groups havebeen substituted by amino functions through a reaction with an amine,such as 2-ethanol amine; (iii) substituting chloromethyl groups on thesurface of the beads with 2-ethanol amine ligands and covalently bindingheparin to the ligands via a material such as a glutare dialdehyde andhexamethylene diisocyanate moiety, and coupling groups consisting ofexcessive pendant aldehyde groups and isocyanate groups with L-asparticacid; or (iv) substituting chloromethyl groups with a material such as2-ethanol amine and ethylene glycol ligands, activating the ligands witha material such as glutare dialdehyde and hexamethylene diisocynate, andcovalently binding hydrophilic polyethylene glycol chains; or (v)covalently binding hydrophilic polyethylene glycol chains throughreacting of sodium alcoholates of the latter with polystyrenechloromethyl groups; or (vi) covalently binding hydrophilic chains ofchitosan through reacting of amino groups of the latter with polystyrenechloromethyl groups; or (vii) substituting chloromethyl groups withligands such as 2-ethanol amine ligands or ethylene glycol ligands,activating the ligands with phosphorus oxychloride, and covalentlybinding hydrophilic moieties such as choline, serine and 2-ethanolamine.

[0142] Further details regarding the composition of particles or beadsof this type can be found in U.S. Pat. No. 5,904,663, which isincorporated herein by reference.

Representative Adsorption Medium EXAMPLE 2

[0143] In another representative embodiment, the adsorption medium 34can include particles or beads formed from a porous hydrophobicdivinylbenzene copolymer with comonomers selected from the group ofstyrene, ethylstyrene, acrylonitrile, and buthyl methacrylate. Suchparticles or beads initially have surface exposed vinyl groups, whichare chemically modified to impart improved biocompatibility, so as toform different surface exposed functional groups, such as polymers of2-hydroxyethyl methacrylate, N-vinylpyrrolidine, N-vinylcaprolactame, orN-acrylamide. The surface exposed functional groups can be products ofoxidation of the vinyl groups to expoxy groups and subsequent additionof polar compounds selected from the group of water, ethylene glycol,primary or secondary amines, and 2-hydroxethyl-amine. Alternatively, thesurface exposed functional groups can be the products of oxidation ofthe vinyl groups to epoxy groups, the subsequent addition of primary orsecondary amines or 2-hydroxyethylamine, and the deposit ofhigh-molecular-weight poly(trifluoroethoxy) phosphazene.

[0144] Further details regarding the composition of particles or beadsof this type can be found in U.S. Pat. No. 6,114,466, which isincorporated herein by reference.

Representative Adsorption Medium EXAMPLE 3

[0145] In another representative embodiment, the adsorption medium 34can include particles or beads formed by polymerization of aromaticdivinyl compounds, such as p- or m-divinylbenzene or mixtures thereof,or their copolymerization with aromatic monovinyl compounds, such asstyrene, methylstyrene, ethylvinylbenzene and vinylbenzylchloride, inthe presence of porogens or mixtures of porogens with properties closeto those of θ-solvents. The porogens can comprise, e.g., cyclohexane,cyclohexanone and other θ-solvents for polystyrene. Alternatively, theporogens can comprise θ-solvents composed of mixtures of a good solventfor polystyrene, such as toluene, benzene, ethylene dichloride,propylene dichloride, tetrachloroethene, dioxane and methylenedichloride, and a non-solvent for polystyrene, such as aliphatichydrocarbons, aliphatic alcohols and aliphatic acids.

[0146] Such hypercrosslinked polymeric adsorbents exhibit a combinationof micropores, mesopores and macropores. The adsorbents may further befunctionalized to enhance their biocompatibility.

[0147] Further details regarding the composition of particles or beadsof this type can be found in U.S. patent application Ser. No.09/143,407, filed Aug. 28, 1998, entitled “Hypercrosslinked PolymericMaterial for Purification of Physiological Liquids of Organism, a Methodfor Producing the Material,” which is incorporated herein by reference.

1. Biocompatibility Index

[0148] Desirably, the adsorption medium 34 is characterized by abiocompatibility index that indicates a physiologically negligibleproduction of cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators in the blood as a result toexposure to the medium. Thus, the adsorption medium 34, which beneficialserves to remove cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators from the blood, does notitself produce an offsetting result of generating additional cytokinesor other species of pro-inflammatory or anti-inflammatory stimulators ormediators.

[0149] The biocompatibility index can be expressed as a dimensionless,numeric quantity, which reflects the degree to which a prescribedbattery of blood characteristics change as a result of contact betweenthe blood and the adsorption medium.

[0150] The prescribed battery of blood characteristics that thebiocompatibility index encompasses rely upon several selected bloodindicators, which quantify, based upon contact between the blood and agiven adsorption medium, (i) the degree to which the numbers of cellularblood components (red blood cells, white blood cells, and platelets) arediminished; (ii) the degree to which leukocytes are activated; (iii) thedegree to which complement activation occurs; (iv) the degree to whichhemolysis occurs; and (v) the degree to which clot formation is induced.

[0151] Indicator (i) is ascertained by Coulter Counter for red bloodcells, white blood cells, and platelets (this indicator this comprisesthree individual indicators).

[0152] Indicator (ii) is ascertained by measuring polymorphonuclearleukocyte elastase (PMN Elastase) concentrations using standardlaboratory techniques (e.g., PMN Elastase, Merck Immunoassay, Merk KgaA,Darmstadt, Germany).

[0153] Indicator (iii) is ascertained by measuring anaphylatoxinC3a-desArg concentrations using standard laboratory techniques (e.g.,Elisa, Progen Biotechnik GmbH, Heidelberg, Germany).

[0154] Indicator (iv) is ascertained by determining the concentrationsof Lactate dehydrogenase (LDH) by standard methods of clinicalchemistry.

[0155] Indicator (v) is ascertained by measuring the concentrations ofthrombin-antithrombin-complex (TAT) using standard laboratory techniques(e.g., Enzygnost-TAT micro Elisa, Dade Behring Marburg GmbH, Marburg,Germany).

[0156] There are therefore a total of seven indicators within thebattery of indicators for the Biocompatibility Index: (1) White BloodCell Count; (2) Red Blood Cell Count; (3) Platelet Count; (4) PMNElastase Concentration; (5) LDH Concentration; (6) C3a-desArgConcentration; and (7) TAT Concentartion. These indicators are listed inTable 1, below.

[0157] In deriving the biocompatibility index, the technician selects ahousing for the media that is made of an acceptable biocompatiblematerial that possesses a biocompatibility comparable to conventionalmedical grade plastics (e.g., polyvinylchloride, polyurethane,polyester, etc) or glass. The technician characterizes the bloodaccording to the battery of indicators after passing the blood throughthe housing in an empty condition, i.e., a housing that contains noabsorption medium.

[0158] The technician uses heparin to anticoagulate the blood in a finalconcentration of 1.0 IU heparin/ml blood. Other types of anticoagulant,such as nafamosat, may be used. However, citrate anticoagulant is not beto used, alone or in combination with the prescribed amount of heparinin deriving the biocompatibility index, because the presence of citratewill mask changes in thrombogenicity and complement activation that mayarise due to contact with the medium, thereby leading to false results.

[0159]FIG. 23 summarizes the results of hemocompatibility testingconducted by Bosch et al of a polyacrylate gel adsorbant material (forthe selective adsorption of low-density lipoproteins), based uponcontact with blood that was anticoagulated either only with heparin orwith a mixture of heparin and citrate (Bosch et al, Artif Organ 17(7)640-52 1993). FIG. 23 demonstrates that, with respect to thethrombogenicity and complement activation indicators—PMN Elastase(indicating the degree to which leukocytes are activated);thrombin-antithrombin-complex TAT (indicating the degree to which clotformation is induced); and anaphylatoxin C3a-desArg (indicating thedegree to which complement activation occurs)—each indicator level readshigh (denoting thrombogenicity and complement activation) when onlyheparin anticoagulant is used. The mixture of citrate with heparin masksthe actual indicator levels in a significant way. FIG. 23 shows that, bybinding calcium (an important co-factor in many hemocompatibilityreactions), the presence of citrate lowers the indicator levels, so thatthey no longer reflect the actual changes in thrombogenicity andcomplement activation that arise due to contact with a given medium.

[0160] The forgoing protocol provides the background or baseline sample,against which the magnitude of changes due to the presence of a givenadsorption medium within the housing can be ascertained and scored.

[0161] In deriving the biocompatibility index, the technician alsocharacterizes the blood according to the battery of indicators afterpassage through the selected housing that contains the absorptionmedium. As before, the technician uses heparin to anticoagulate theblood in a final concentration of 1.0 IU heparin/ml blood. For thereasons stated above, citrate anticoagulant is not be to used inderiving the biocompatibility index, alone or in combination with theprescribed amount of heparin.

[0162] In carrying out the steps just described, the technicianassembles a test system 300 as shown in FIG. 16. The test system 300comprises two parallel channels 302 and 304 connected by a y-connector306 to a blood line 308. A housing 310 and 312 is coupled in eachchannel, respectively 302 and 304. The housing 310 is empty (i.e., freeof adsorption medium), and the housing 312 contains the adsorptionmedium 314. The blood line 308 can be coupled, e.g., to the antecubitalvein of a healthy volunteer. The access system desirably allows forcontinuous heparinization at the tip of the inserted cannula or needleto avoid systemic heparinzation. Peristaltic pumps P1 and P2 in thechannels 302 and 304 (or a single, double tube peristaltic pump) conveythe blood through the housings 310 and 314. An infusion pump P3 metersheperin, to achieve a final heparin concentration of 1.0 IU/ml.

[0163] The pumps P1, P2, and P3 are started simultaneously. On-lineblood perfusion of the two channels 302 and 304 is maintained througheach housing 310 and 312. The speeds of the pumps P1 and P2 are adjustedto 10 mL/min through each housing 310 and 312. Blood samples arecollected at the outlet of each channel 302 and 304 after 5, 10, 15, and25 minutes of perfusion directly into specially prepared polypropylenevials V stored on ice. The blood samples are analyzed for the selectedindicators immediately. Blood counts are corrected for hemodilution dueto the addition of heparin.

[0164] The cell count indicators are corrected by the following formula:X_(corr)=X times (hct_(pre)/hct_(t), where X_(corr) is the correctedparameter, X is the measured value of the parameter at time point t,hct_(pre) is the hematocit pre value (t=0), and hct_(t) is thehematocrit at time point t.

[0165] The plasma indicators for PMN Elastase Concentration, LDHConcentration, C3a-desArg Concentration, and TAT Concentartion arecorrected by the following formula: X_(corr)=X times(1-hct_(t)/1-hct_(pre), where X_(corr) is the corrected plasmaparameter, X is the measured value of the plasma parameter at time pointt, hct_(pre) is the hematocit pre value (t=0), and hct_(t) is thehematocrit at time point t.

[0166] The technician reviews the assembled indicators to ascertain, foreach indicator, the maximum difference between the indicator values over25 ml of blood flow of the blood passed through the housing 310 (withoutthe medium—baseline) and the blood passed through the housing 312containing the medium 314. For each indicator, the technician expressesthe maximum change as a percentage, relative to the baseline value.

[0167] The technician then scores the percentage change for eachindicator as a dimensionless numeric quantity 1, 2, or 3, depending uponthe magnitude of the percentage change, in accordance with Table 1. InTable 1, a percentage change equal to or less than a prescribed minimumfor a given indicator is scored as a 1, signifying a most desirabledegree of biocompatibility. In Table 1, a percentage change greater thana prescribed maximum for a given indicator is scored as a 3, signifyinga least desirable degree of biocompatibility. In Table 1, a percentagechange between the prescribed minimum and the prescribed maximum for agiven indicator is scored as a 2, signifying an acceptable degree ofbiocompatibility, albeit not the most desired. TABLE 1 TheBiocompatibility Index Score Table Numeric Scores 1 2 3 (Signifying(Signifying (Signifying Most an a Least Desired Acceptable DesiredDegree of Degree of Degree of Blood Biocompati- Biocompati- Biocompati-Indicator bility) bility) bility) Loss of White Maximum Maximum MaximumBlood Cells Difference Difference Difference Between Between BetweenBaseline Baseline and Baseline and and Medium Medium (25 Medium (25 (25ml) ml) ml) ≦15% >15% >20% ≦20% Loss of Red Maximum Maximum MaximumBlood Cells Difference Difference Difference Between Between BetweenBaseline Baseline and Baseline and and Medium Medium (25 Medium (25 (25ml) ml) ml) ≦15% >15% >20% ≦20% Loss of Maximum Maximum MaximumPlatelets Difference Difference Difference Between Between BetweenBaseline Baseline and Baseline and and Medium Medium (25 Medium (25 (25ml) ml) ml) ≦15% >15% >20% ≦20% PMN Elastase Maximum Maximum MaximumConcentration Difference Difference Difference Between Between BetweenBaseline Baseline and Baseline and and Medium Medium (25 Medium (25 (25ml) ml) ml) ≦15% >15% >20% ≦20% LDH Maximum Maximum MaximumConcentration Difference Difference Difference Between Between BetweenBaseline Baseline and Baseline and and Medium Medium (25 Medium (25 (25ml) ml) ml) ≦15% >15% >20% ≦20% C3a-desArg Maximum Maximum MaximumConcentration Difference Difference Difference Between Between BetweenBaseline Baseline and Baseline and and Medium Medium (25 Medium (25 (25ml) ml) ml) ≦20% >20% >25% ≦25% TAT Maximum Maximum MaximumConcentration Difference Difference Difference Between Between BetweenBaseline Baseline and Baseline and and Medium Medium (25 Medium (25 (25ml) ml) ml) ≦15% >15% >20% ≦20%

[0168] After scoring each indicator with a numeric quantity of 1, 2, or3, the technician adds the numeric quantities scored for all theindicators to obtain a total. The total constitutes the biocompatibilityindex for the given 10 adsorption medium.

[0169] The Biocompatibility Index for a given material is a reliableindicator of blood compatibility. There is a strong correlation betweenthe value of the Biocompatibility Index, derived in the manner justdescribed, and the ability of given material to selectively removetargeted proteins from the blood without significant destruction ofcellular components and hemolysis and without significant clot formation(i.e., low thrombogenicity). Materials characterized by aBiocompatibility Index equal to or less than 14, and, most desirably, bya Biocompatible Index not greater than 7, contact the blood with nosignificant loss of blood cells, no significant hemolysis, nosignificant activation of luekocytes or monocytes, and, at most, onlyvery mild complement activation, even with the use of heparin as thesole anticoagulant. Because such materials are not likely to induce thegeneration of cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators, they are well suited for useto remove cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators from the blood, bloodproducts, or physiologic fluids.

[0170] On the other hand, materials characterized by a BiocompatibilityIndex greater than 14, contact the blood with adverse effects in termsof significant blood cell loss, or significant hemolysis, or significantleukocyte activation, or significant compliment activation, orsignificant combinations thereof. Such materials are therefore likely toinduce the generation of cytokines or other species of pro-inflammatoryor anti-inflammatory stimulators or mediators and are not acceptable foruse to remove cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators.

[0171] E. Multiple Functionality

[0172] As previously discussed, the devices, systems, and methods aredirected to the removal of cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators to reducelevels of such agents in the blood in situations where abnormal levelsof such agents occur, or during events that do induce or have thepotential for inducing abnormal production of cytokines or other speciesof pro-inflammatory or anti-inflammatory stimulators or mediators. Inthis way, the devices, systems, and methods serve to control, reduce, oralleviate the severity of many physiologic conditions and disease statesthat are associated with abnormal levels of cytokines or other speciesof pro-inflammatory or anti-inflammatory stimulators or mediators.

[0173] It should be appreciated that the devices, systems, and methodscan be adapted to perform other functions in tandem with removal ofcytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators as well.

[0174]FIG. 13 shows a device 82 that is usable in association with thesystems and methods previously discussed to provide adsorption of bothcytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators and other material or materials from the blood.The device 82 includes a first compartment 84, which contains theadsorption medium 34, previously described, to remove cytokines or otherspecies of pro-inflammatory or anti-inflammatory stimulators ormediators. The device 82 includes a second compartment 86, whichcontains a different medium 88, which can comprise an adsorption mediumor an ion exchange medium, to remove another type of material from theblood. A partition 90 in the device 82 (e.g., made of a mesh material toaccommodate fluid flow) separates the first compartment 84 from thesecond compartment 86. In use, the blood is conveyed into the device 82through an inlet 92. The blood passes in succession through theadsorption medium 34 and the different, second medium 88. The bloodexits the device 82 through an outlet 94. During passage, cytokines orother species of pro-inflammatory or anti-inflammatory stimulators ormediators are removed from the blood by the adsorption medium 34 and theother material is removed from the blood by the different, second medium88. The order of passage through the mediums 34 and 88 can be reversed.

[0175] The adsorption medium 88 can be variously constructed dependingupon the material intended to be removed.

[0176] 1. Removal of LPS EndoToxin

[0177] For example, the adsorption medium 88 can be constructed toremove LPS endotoxin, which is released into the blood of an individualsuffering from a gram-negative bacterial infection. In the blood, LPSendotoxin coalesce into vesicles ranging in size from 300,000 to1,000,000 daltons. Phosphoryl groups contained within the LPS endotoxingive it an overall negative charge at physiologic pH. The release of LPSendotoxin into the blood can cause fever, low blood pressure, and organfailure.

[0178] As previously discussed, the presence of LPS endotoxin alsostimulates the secretion of cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators. Thepresence of LPS endotoxin can therefore also contribute to increasedlevels of cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators, and even to the onset of aseptic shock episode.

[0179] In the illustrated embodiment (see FIG. 13), the adsorptionmedium 88 includes a group of polymer particles 96 comprisinghydrophobic porous core to which LPS endotoxin binds. To provide areliable interaction between the endotoxin and the polymer core, thepolymer particles have pores of a corresponding large size. For example,the size of the pores can be within the range of 20 to 150 nm, andpreferably between 30 and 100 nm. The polymeric particles 96 are thuspredominantly macroporous.

[0180] The polymer for the core of the particles 96 can be selected fromthe same group of materials as the polymer for the core 78 of theparticles 76 of the adsorption medium 34, as before described.

[0181] Like the particles 76 of the first adsorption medium 34, theparticles 96 of the adsorption medium 88 desirable include a hydrophiliccoating or shell to provide biocompatibility, which is also desirablycharacterized by a high biocompatibility index. The coating material forthe particles 96 can be selected from the same group of materials as thecoating 80 for the particles 76 of the first adsorption medium 34.

[0182] In addition, the polymer particles 96 can also possess positivelycharged functional groups on the surface of the hydrophobic pores tofurther attract endotoxin through an ionic interaction. The amount ofthese positively charged groups desirably remains low, preferably below1 meq/ml. Thus, the overall hydrophobic nature of the core of thepolymeric particle is not compromised, so that hydrophobic interactionsstill remain the major mechanism of adsorption of LPS endotoxin. Thepositively charged functional groups covalently bonded to the surface ofthe pores of the polymeric particles 96 can be selected from the groupcomposed of amino-, methylamino-, ethylamino-, dimethylamino-,diethylamino-, ethanolamino-, diethanolamino-, polyethylenimino-groups,imidazole, histamine, or basic amino acids as lysine, arginine,histidine.

[0183] 2. Removal of Other Materials

[0184] The adsorption medium 88 can also be composed to selectivelyadsorb other targeted proteins or toxins that can be released into theblood as a result of injury or trauma, e.g., myoglobin, which can bereleased during a crush injury. The adsorption medium 88 can also becomposed to selectively adsorb targeted chemical moieties that can bereleased into the blood as a result of injury or trauma, e.g.,potassium, which can be released with myoglobin during a crush injury.

[0185] The device 18 or 30 can also be used in combination with otherdevices that remove materials from the blood other than by selectiveadsorption, e.g., by ion exchange effects.

[0186] III. Systems and Methods for Removing Cytokines or Other Speciesof Pro-inflammatory or Anti-inflammatory Stimulators or Mediators fromPhysiologic Fluids

[0187]FIG. 14 shows an embodiment of a system 100 for removing cytokinesor other species of pro-inflammatory or anti-inflammatory stimulators ormediators from a physiologic fluid. In this embodiment, the physiologicfluid comprises fresh peritioneal dialysis solution that has beenregenerated from spent peritoneal dialysis solution.

[0188] As shown in FIG. 14, the system 100 is configured for conductinga form of automated peritoneal dialysis. The system 100 includes acycler 114, to automatically infuse, dwell, and drain peritonealdialysis solution to and from the patient's peritoneal cavity 120,typically at night while the patient is asleep.

[0189] The system 100 includes a peritoneal dialysis solution flow set112 that establishes communication between the system 100 and theperitoneal cavity 120 of the patient. The cycler 114 interacts with theflow set 112, to pump peritoneal dialysis solution into and out of thepatient's peritoneal cavity 120 in prescribed infuse, dwell, and draincycles.

[0190] The flow set 112 includes an in-line regeration module 122. Thecycler 114 circulates peritoneal dialysis solution, removed from thepatient's peritoneal cavity 120, into the module 122 The cycler 114 alsocirculates a regeneration solution containing, e.g., electrolytes and/orbuffering materials, from a source 115 into the module 122.

[0191] The module 122 includes a component, e.g., a membrane, thattransports waste and uremic toxins from the spent peritoneal dialysissolution into the regeneration solution, while also transportingelectrolytes and buffering materials from the regeneration solution 115into the peritoneal dialysis solution. Typically, the regenerationfluid, laden with toxins and depleted of electrolytes and buffers, issent to waste.

[0192] The module 122 thereby performs on-line regeneration ofperitoneal dialysis solution. Upon regeneration, the cycler 114re-circulates the peritoneal dialysis solution back to the peritonealcavity 120 of the patient.

[0193] The spent peritoneal dialysis solution may carry cytokines orother species of pro-inflammatory or anti-inflammatory stimulators ormediators generated while the solution dwelled within the peritonealcavity of the patient. Extracorporeal processing of the spent solutionby the cycler 114 can also trigger additional production of cytokines orother species of pro-inflammatory or anti-inflammatory stimulators ormediators.

[0194] The system 100 therefore includes a device 130 that removescytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators from the physiologic peritoneal dialysissolution prior to its return to the patient's peritoneal cavity 120. Thedevice 130 can be coupled to the system 100 either upstream ordownstream of the regeneration module 122. In this arrangement,cytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators are removed from the peritoneal dialysissolution either before or after regeneration, and prior to return to theregenerated solution to the peritoneal cavity 120 of the patient. Thisleads to overall reduced levels of cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators in theperitoneal dialysis patient.

[0195] It should be appreciated that the device 122 can be used in otherperitoneal dialysis modalities where regeneration of peritoneal dialysissolution is performed.

[0196] Body fluids that are removed from and then recycled back to thebody during a given treatment modality can also carry cytokines or otherspecies of pro-inflammatory or anti-inflammatory stimulators ormediators, or cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators can be generated as a resultof such treatment modalities. Treatment systems and methods exist forremoving and recycling such fluids, e.g., lymphatic fluid, synovialfluid, spinal fluid, or cerebrospinal fluid. The devices, systems, andmethods that embody this aspect of the invention, as just discussed inthe context of peritoneal dialysis, can likewise be used in associationwith such treatment modalities, to remove cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators from thebody fluids before, during, or after other forms of primary treatment.

[0197]FIG. 15 shows another embodiment of a system 200 for removingcytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators from a physiologic fluid. In this embodiment,the physiologic fluid comprises preservation solution 206 for aharvested organ 202 awaiting transplantation.

[0198] As shown in FIG. 15, the system 200 includes a bath 204 holdingthe organ 202. The preservation solution 206 is circulated from a source208 through the bath 204 and through the organ 202. FIG. 15 depicts aharvested kidney 202, but the organ can be any solid organ harvested fortransplant.

[0199] The organ 202 may generate cyctokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators whileimmersed in the bath 204. The cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators will, inturn enter the preservation solution 206 contacting and perfusing theorgan 202. Circulation of the preservation solution may also triggeradditional production of cytokines or other species of pro-inflammatoryor anti-inflammatory stimulators or mediators.

[0200] The system 200 therefore includes a device 230 that removescytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators from the preservation solution. The device 230can be coupled to the system 200 either upstream or downstream of thebath 204. In this arrangement, cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators areremoved from the preservation solution, so that the overall populationof cytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators to which the organ 202 is exposed prior totransplantation is minimized. This leads to overall reduced levels ofcytokines or other species of pro-inflammatory or anti-inflammatorystimulators or mediators in the patient who receives the organtransplant.

[0201] Either device 120 or 230 can be constructed in generally the samefashion already described with respect to devices 18 or 30.

EXAMPLE 1 Blood Purification Using an Adsorption Medium to RestoreImmunologic Stability

[0202] A study was conducted to demonstrate the ability of abiocompatible adsorption medium to selectively adsorb cytokines (TNF,IL-6, and IL-10) from the blood. The medium comprised particles (asgenerally shown in FIG. 12) formed of a core of hydrophobic, crosslinkedporous divinylbenzene material coated with a thin, permeablebiocompatible hydrophilic polyvinylpyrrolidone material. The corematerial of the particles possessed a mean pore size of about 16 nm. Theparticles were contained within a housing (as generally shown in FIG. 3)and presented a surface area to blood flow of about 650 sq.mg. Themedium was obtained from RenalTech International, New York, N.Y.(BetaSorb™ Adsorption Medium).

[0203] The medium was tested in an experiment using in three animalssubjected to cecal ligation and puncture (CLP) 18 hrs earlier. Theanimals tolerated treatment with the medium without difficulty. Thecytokine response was characterized over the four hours of treatment(see FIG. 17).

[0204] The results demonstrate that the medium removed all threecytokines from the blood. As FIG. 17 shows, there was a flattening outor even downward trend in the concentrations of TNF, IL-6 and IL-10 (inorder to keep the scales similar, the units for TNF in FIG. 17 arepg/ml, IL-6 are ng/dl, and IL-10 are pg/cl). Previous experience withthis model has shown a progressive increases in IL-6 and IL-10 over asimilar time period and a more persistent TNF signal.

EXAMPLE 2 Biocompatibility Index of the Adsorption Medium

[0205] The adsorption medium employed in Example 1 was subjected to theprescribed battery of tests under the biocompatibility index testprotocol described above. The blood drawn from six individual healthydonors was subjected to the test protocol and the test results wereaveraged.

[0206]FIGS. 18A, 18B, and 18C show the average variations in blood cellcounts for red blood cells, white blood cells, and platelets,respectively, incrementally during passage of 25 ml of the blood throughthe treatment device containing the medium. With respect to red bloodcells, white blood cells, and platelets, the maximum difference betweenthe base line (line S.K./A) and the medium (line S.K./B) was less than15%.

[0207]FIG. 19 shows the average variations in PMN elastaseconcentrations (indicative of leukocyte activation) incrementally duringpassage of 25 ml of the blood through the treatment device containingthe medium. The maximum difference between the based line (line S.K./A)and the medium (line S.K./B) was less than 15%.

[0208]FIG. 20 shows the average variations in LDH concentrations(indicative of hemolysis) incrementally during passage of 25 ml of theblood through the treatment device containing the medium. The maximumdifference between the based line (line S.K./A) and the medium (lineS.K./B) was less than 15%.

[0209]FIG. 21 shows the average variations in C3a-desArgconcentrations(indicative of complement activation) incrementally duringpassage of 25 ml of the blood through the treatment device containingthe medium. One donor experienced a rapid increase in the C3a-desArglevel from 86 up to 822 μg/L due to clotting in the test system. Theother five donors (who experienced no clotting in the test system)underwent more moderate increases, with a mean increase of from 113 to392 μg/L. The maximum difference between the based line (line S.K./A)and the medium (line S.K./B) was greater than 25%.

[0210]FIG. 22 shows the average variations in TAT concentrations(indicative of coagulation) incrementally during passage of 25 ml of theblood through the treatment device containing the medium. The maximumdifference between the based line (line S.K./A) and the medium (lineS.K./B) was less than 15%.

[0211] The following table lists the scoring the results for theindications as the dimensionless quantities 1, 2, and 3. Numeric Scores1 2 3 (Signifying (Signifying (Signifying Most an a Least DesiredAcceptable Desired Degree of Degree of Degree of Blood Biocompati-Biocompati- Biocompati- Indicator bility) bility) bility) Loss /of 1White Blood Cells Loss of Red 1 Blood Cells Loss of 1 Platelets PMNElastase 1 Concentration LDH 1 Concentration C3a-desArg 3 ConcentrationTAT 1 Concentration

[0212] The Biocompatibility Index for the Medium is 9, which indicatesthe medium can contact the blood with no significant loss of bloodcells, no significant hemolysis, no significant activation of luekocytesor monocytes, and, at most, only moderate complement activation, evenwith the use of heparin as the sole anticoagulant. Because suchmaterials are not likely to induce the generation of cytokines, they arewell suited for use to remove cytokines from the blood, blood products,or physiologic fluids.

[0213] Various features of the invention are set forth in the followingclaims.

We claim:
 1. A blood processing system comprising a blood componentproduct harvested from the blood drawn from an individual, a containersized to receive the blood component product, and a device communicatingwith the container to remove cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators from theblood component product.
 2. A system according to claim 1 wherein theblood component product includes a red blood cell component.
 3. A systemaccording to claim 1 wherein the blood component product includes aplatelet component.
 4. A system according to claim 1 wherein the bloodcomponent product includes a white blood cell component.
 5. A systemaccording to claim 1 wherein the blood component product includes aplasma component.
 6. A system according to claim 1 wherein the deviceincludes an adsorption medium to remove cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators.
 7. Asystem according to claim 6 wherein the adsorption medium ischaracterized by a Biocompatibility Index of not greater than
 14. 8. Asystem according to claim 7 wherein the Biocompatibility Index is notgreater than
 7. 9. A system according to claim 1 or 2 wherein the deviceincludes an adsorption medium to remove cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators, theadsorption medium comprising a polymeric material.
 10. A systemaccording to claim 9 wherein the polymeric material comprises particlesprepared by polymerization or copolymerization of a monomer selectedfrom a group consisting of styrene, ethylstyrene, α-methylstyrene,divinylbenzene, di isopropenyl benzene, trivinylbenzene, and alkylmethacrylate.
 11. A system according to claim 9 wherein the polymericmaterial comprises particles formed from crosslinked polystyrene-typeresins having a surface modified to minimize activation of bloodcomplement system.
 12. A system according to claim 9 wherein thepolymeric material comprises particles formed from a porous hydrophobicdivinylbenzene copolymer having a surface modified to include surfaceexposed functional groups selected from the group of polymers of2-hydroxyethyl methacrylate, N-vinylpyrrolidine, N-vinylcaprolactame andN-acrylamide.
 13. A system according to claim 9 wherein the polymericmaterial comprises particles formed by polymerization of aromaticdivinyl compounds or their copolymerization with aromatic monovinylcompounds in the presence of porogens or mixtures of porogens withproperties close to those of θ-solvents.
 14. A system for collecting ablood component product comprising means for processing the blood drawnfrom an individual into a blood component product, a storage container,means for collecting the blood component product in the storagecontainer, and means for removing cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators from theblood component product before, during, or after its collection in thestorage container.
 15. A system according to claim 14 wherein the bloodcomponent product includes a red blood cell component.
 16. A systemaccording to claim 14 wherein the blood component product includes aplatelet component.
 17. A system according to claim 14 wherein the bloodcomponent product includes a white blood cell component.
 18. A systemaccording to claim 14 wherein the blood component product includes aplasma component.
 19. A system according to claim 14 wherein the meansfor removing cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators includes an adsorption mediumto remove cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators.
 20. A system according toclaim 19 wherein the adsorption medium is characterized by aBiocompatibility Index of not greater than
 14. 21. A system according toclaim 20 wherein the Biocompatibility Index is not greater than
 7. 22. Asystem according to claim 14 wherein the device includes an adsorptionmedium to remove cytokines or other species of pro-inflammatory oranti-inflammatory stimulators or mediators, the adsorption mediumcomprising a polymeric material.
 23. A system according to claim 22wherein the polymeric material comprises particles prepared bypolymerization or copolymerization of a monomer selected from a groupconsisting of styrene, ethylstyrene, α-methylstyrene, divinylbenzene, diisopropenyl benzene, trivinylbenzene, and alkyl methacrylate.
 24. Asystem according to claim 22 wherein the polymeric material comprisesparticles formed from crosslinked polystyrene-type resins having asurface modified to minimize activation of blood complement system. 25.A system according to claim 22 wherein the polymeric material comprisesparticles formed from a porous hydrophobic divinylbenzene copolymerhaving a surface modified to include surface exposed functional groupsselected from the group of polymers of 2-hydroxyethyl methacrylate,N-vinylpyrrolidine, N-vinylcaprolactame and N-acrylamide.
 26. A systemaccording to claim 22 wherein the polymeric material comprises particlesformed by polymerization of aromatic divinyl compounds or theircopolymerization with aromatic monovinyl compounds in the presence ofporogens or mixtures of porogens with properties close to those ofe-solvents.
 27. A method for collecting a blood component productcomprising the steps of processing the blood drawn from an individualinto a blood component product, collecting the blood component productin a storage container, and removing cytokines or other species ofpro-inflammatory or anti-inflammatory stimulators or mediators from theblood component product before, during, or after its collection in thestorage container.
 28. A method according to claim 27 wherein the bloodcomponent product includes a red blood cell component.
 29. A methodaccording to claim 27 wherein the blood component product includes aplatelet component.
 30. A method according to claim 27 wherein the bloodcomponent product includes a white blood cell component.
 31. A methodaccording to claim 27 wherein the blood component product includes aplasma component.
 32. A method according to claim 27 wherein theremoving step includes use of an adsorption medium to remove cytokinesor other species of pro-inflammatory or anti-inflammatory stimulators ormediators.
 33. A method according to claim 32 wherein the adsorptionmedium comprises a polymeric material.
 34. A method according to claim33 wherein the polymeric material comprises particles prepared bypolymerization or copolymerization of a monomer selected from a groupconsisting of styrene, ethylstyrene, α-methylstyrene, divinylbenzene, diisopropenyl benzene, trivinylbenzene, and alkyl methacrylate.
 35. Amethod according to claim 33 wherein the polymeric material comprisesparticles formed from crosslinked polystyrene-type resins having asurface modified to minimize activation of blood complement system. 36.A method according to claim 33 wherein the polymeric material comprisesparticles formed from a porous hydrophobic divinylbenzene copolymerhaving a surface modified to include surface exposed functional groupsselected from the group of polymers of 2-hydroxyethyl methacrylate,N-vinylpyrrolidine, N-vinylcaprolactame and N-acrylamide.
 37. A methodaccording to claim 33 wherein the polymeric material comprises particlesformed by polymerization of aromatic divinyl compounds or theircopolymerization with aromatic monovinyl compounds in the presence ofporogens or mixtures of porogens with properties close to those ofθ-solvents.